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[[Image: | ==ORALLY ACTIVE 2-AMINO THIENOPYRIMIDINE INHIBITORS OF THE HSP90 CHAPERONE== | ||
<StructureSection load='2wi6' size='340' side='right' caption='[[2wi6]], [[Resolution|resolution]] 2.18Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2wi6]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WI6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WI6 FirstGlance]. <br> | |||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZZ6:2-AMINO-4-(2,4-DICHLOROPHENYL)-N-ETHYLTHIENO[2,3-D]PYRIMIDINE-6-CARBOXAMIDE'>ZZ6</scene><br> | |||
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1yes|1yes]], [[1uy9|1uy9]], [[2cdd|2cdd]], [[1byq|1byq]], [[1osf|1osf]], [[2bsm|2bsm]], [[1uy8|1uy8]], [[2bug|2bug]], [[2uwd|2uwd]], [[2bt0|2bt0]], [[1yer|1yer]], [[1uyg|1uyg]], [[2ccu|2ccu]], [[2bz5|2bz5]], [[2ccs|2ccs]], [[1uyf|1uyf]], [[1yc3|1yc3]], [[1uyi|1uyi]], [[1uyd|1uyd]], [[2byi|2byi]], [[1uy6|1uy6]], [[2vci|2vci]], [[2vcj|2vcj]], [[1yc4|1yc4]], [[2c2l|2c2l]], [[1uyh|1uyh]], [[1uyk|1uyk]], [[2cct|2cct]], [[1uyl|1uyl]], [[1uye|1uye]], [[1yc1|1yc1]], [[1uy7|1uy7]], [[1uyc|1uyc]], [[1yet|1yet]], [[2jjc|2jjc]], [[2byh|2byh]], [[2wi4|2wi4]], [[2wi2|2wi2]], [[2wi7|2wi7]], [[2wi3|2wi3]], [[2wi1|2wi1]], [[2wi5|2wi5]]</td></tr> | |||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2wi6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wi6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2wi6 RCSB], [http://www.ebi.ac.uk/pdbsum/2wi6 PDBsum]</span></td></tr> | |||
<table> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/wi/2wi6_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors, which were designed by combining structural elements of distinct low affinity hits generated from fragment-based and in silico screening exercises in concert with structural information from X-ray protein crystallography. Examples from this series have high affinity (IC(50) = 50-100 nM) for Hsp90 as measured in a fluorescence polarization (FP) competitive binding assay and are active in human cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Several examples (34a, 34d and 34i) caused tumor growth regression at well tolerated doses when administered orally in a human BT474 human breast cancer xenograft model. | |||
Combining Hit Identification Strategies: Fragment-Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-d]pyrimidine Inhibitors of the Hsp90 Molecular Chaperone.,Brough PA, Barril X, Borgognoni J, Chene P, Davies NG, Davis B, Drysdale MJ, Dymock B, Eccles SA, Garcia-Echeverria C, Fromont C, Hayes A, Hubbard RE, Jordan AM, Jensen MR, Massey A, Merrett A, Padfield A, Parsons R, Radimerski T, Raynaud FI, Robertson A, Roughley SD, Schoepfer J, Simmonite H, Sharp SY, Surgenor A, Valenti M, Walls S, Webb P, Wood M, Workman P, Wright L J Med Chem. 2009 Jul 17. PMID:19610616<ref>PMID:19610616</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Heat Shock Proteins|Heat Shock Proteins]] | *[[Heat Shock Proteins|Heat Shock Proteins]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Barril, X.]] | [[Category: Barril, X.]] | ||
Revision as of 12:13, 29 September 2014
ORALLY ACTIVE 2-AMINO THIENOPYRIMIDINE INHIBITORS OF THE HSP90 CHAPERONEORALLY ACTIVE 2-AMINO THIENOPYRIMIDINE INHIBITORS OF THE HSP90 CHAPERONE
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedInhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors, which were designed by combining structural elements of distinct low affinity hits generated from fragment-based and in silico screening exercises in concert with structural information from X-ray protein crystallography. Examples from this series have high affinity (IC(50) = 50-100 nM) for Hsp90 as measured in a fluorescence polarization (FP) competitive binding assay and are active in human cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Several examples (34a, 34d and 34i) caused tumor growth regression at well tolerated doses when administered orally in a human BT474 human breast cancer xenograft model. Combining Hit Identification Strategies: Fragment-Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-d]pyrimidine Inhibitors of the Hsp90 Molecular Chaperone.,Brough PA, Barril X, Borgognoni J, Chene P, Davies NG, Davis B, Drysdale MJ, Dymock B, Eccles SA, Garcia-Echeverria C, Fromont C, Hayes A, Hubbard RE, Jordan AM, Jensen MR, Massey A, Merrett A, Padfield A, Parsons R, Radimerski T, Raynaud FI, Robertson A, Roughley SD, Schoepfer J, Simmonite H, Sharp SY, Surgenor A, Valenti M, Walls S, Webb P, Wood M, Workman P, Wright L J Med Chem. 2009 Jul 17. PMID:19610616[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCACategories:
- Homo sapiens
- Barril, X.
- Borgognoni, J.
- Brough, P A.
- Chene, P.
- Davies, N G.M.
- Davis, B.
- Drysdale, M J.
- Dymock, B.
- Eccles, S A.
- Fromont, C.
- Garcia-Echeverria, C.
- Hayes, A.
- Hubbard, R E.
- Jordan, A M.
- Massey, A.
- Merret, A.
- Padfield, A.
- Parsons, R.
- Radimerski, T.
- Raynaud, F I.
- Robertson, A.
- Roughley, S D.
- Rugaard-Jensen, M.
- Schoepfer, J.
- Simmonite, H.
- Surgenor, A.
- Valenti, M.
- Walls, S.
- Webb, P.
- Wood, M.
- Workman, P.
- Wright, L M.
- Atp-binding
- Atpase
- Chaperone
- Heat shock
- Hsp90
- Nucleotide-binding
- Phosphorylation
- Pu3
- Stress response